Product Monograph

Home , Diatrizoate, Iodinated contrast, Ioxaglic acid

PRODUCT MONOGRAPH

Proprietary name: Hexabrix® 200

Proper name: Ioxaglate Meglumine 24.6% and Ioxaglate Sodium 12.3%

Proprietary name: Hexabrix® 320

Proper name: Ioxaglate Meglumine 39.3% and Ioxaglate Sodium 19.6%

Pharmacology classification: Ionic, low osmolality, water soluble radiopaque contrast medium for intravascular use.

GUERBET BP 57400 95943 Roissy CdG Cedex FRANCE

Control No. 162948 Revised: April 4, 2013 1

PRODUCT MONOGRAPH

NAME OF DRUG

HEXABRIX® 200

(Ioxaglate Meglumine 24.6% and Ioxaglate Sodium 12.3%)

HEXABRIX® 320

(Ioxaglate Meglumine 39.3% and Ioxaglate Sodium 19.6%)

Therapeutic or Pharmacological Classification

Ionic, Low Osmolality, Water Soluble, Radiopaque Contrast Medium for Intravascular Use

ACTIONS AND CLINICAL PHARMACOLOGY

Following intravascular injection, Hexabrix is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In patients with normal renal function, the alpha and beta half lives of Hexabrix 320 were 12 and 92 minutes, respectively.

Following the intravenous administration of 50 mL of Hexabrix 320 in normal volunteers, the mean peak plasma concentration occurred at two minutes, reaching a concentration of 2.13 mg/mL. Fifty percent of the intravenously administered dose was recovered in the urine at 2 hours, and approximately 90% was recovered at 24 hours.

Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Ioxaglate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys. The liver and small intestine provide the major alternate route of excretion. Hexabrix appears to be excreted primarily by glomerular filtration but some tubular re-absorption may occur. In the rat, biliary excretion plays a major role (up to 30%). As with iothalamate, in patients, especially with renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Occasional visualization of the gallbladder following administration of Hexabrix is suggestive of such a mechanism. Heterogenic excretion to a lesser extent occurs via the saliva, sweat and colon.

Studies in the pregnant mouse have shown that ioxaglate and diatrizoate are capable of crossing the placental barrier and invading fetal tissue.

Angiography

Hexabrix opacifies vessels along the path of injection until such time as hemodilution renders them no longer visible. The digital subtraction technique allows arterial visualization following intravenous injection of Hexabrix 320, or following intraarterial injection of the lower concentration contrast media, Hexabrix 200. The joint spaces, as well as the uterus and fallopian tubes, may be visualized by direct injection of the contrast medium into those structures.

Computerized Tomography of the Head

When Hexabrix is used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is related to the amount of iodine administered. Rapid infusion of the entire dose amount yields peak blood iodine concentrations immediately following the infusion, which fall rapidly over the next five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibrium with the extracellular compartments is reached by about ten minutes; thereafter, the fall becomes exponential. With respect to tumors, maximum contrast enhancement frequently occurs at a time following peak blood iodine concentration. This delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type and vascularity of the tumor. This lag suggests that the contrast enhancement of the image is at least in part dependent on the passage of iodine through the defective blood-brain barrier and on its accumulation within the lesion and outside the blood pool. The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool. Studies indicate that equilibriated blood iodine levels of 100 mg% are required in most cases to achieve adequate contrast enhancement. This can be accomplished by the rapid infusion of approximately 30 to 40 grams of iodine.

In brain scanning, the contrast medium does not accumulate in normal brain tissue due to the presence of the "blood-brain barrier". The increase in X-ray absorption in the normal brain is due to the presence of the contrast agent within the blood pool. A break in the blood-brain barrier, such as occurs in malignant tumors of the brain allows accumulation of the contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium.

Computerized Tomography of the Body

In non-neural tissues (during CT of the body), Hexabrix diffuses rapidly from the vascular to the extra-vascular space. Increase in X-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different from that in the brain.

Enhancement of CT with Hexabrix may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT.

The pharmacokinetics of Hexabrix in normal and abnormal tissue has been shown to be variable. Contrast enhancement appears to be greatest within 30 - 90 seconds after bolus administration, thus greatest enhancement can be detected by a series of consecutive 2 - 3 second scans ("Dynamic CT Scanning") during this time period. Dynamic scanning may improve enhancement and diagnostic assessment of tumors and other lesions such as an abscess, occasionally revealing more extensive disease. A cyst, or similar non-vascularized lesion may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; the non-vascularized lesions show no change in CT number, the vascularized lesions would show an increase. The latter might be benign, malignant or normal, but it is unlikely that it would be a cyst, hematoma or other non-vascularized lesion. 4

Due to the low osmolality of Hexabrix, the increase in circulating blood volume is less than that caused by traditional iodinated contrast agents. This was demonstrated by hematocrit determinations in animals and is consistent with mean values for cardiac output observed in controlled clinical studies. In some double blind clinical trials, Hexabrix produced statistically significant reductions in some hemodynamic changes and discomfort (pain) when compared to contrast agents with higher osmolalities and different iodine content and concentration.

Hexabrix produced significant but transient reductions in respiratory rate, increase or decrease in pulse rate, significant post-injection increases or decreases in systolic and diastolic blood pressure, LVSP, RVSP, LVEDP, RVEDP, and pulmonary artery pressure.

Statistically significant laboratory parameter changes have occurred, such as decreased HB, RBC, HCT, relative lymphopenia, increased SGPT, CPK, LDH, bilirubin and decreased serum Na, Cl, K and Ca. With respect to ECG changes, arrhythmias and S-T wave changes, these showed a similar incidence with Hexabrix 320 and Na meglumine diatrizoate 37% I.

Two studies of the action of Hexabrix 320 on the EEG have been carried out. In one, changes were seen in only 1 patient out of 16, who had shown Stage 1 coma and evidence of intracranial hypertension prior to the examination. In the other transient low voltage delta waves were noted 5 times in 38 injections.

Effects of Hexabrix on thyroid function consisted of significant but slight rises in hormonal iodine and T3 and minor decreases in rT3. There were no changes in TSH. Both Hexabrix and diatrizoic acid activated both the classical and alternative complement pathways in vitro.

Hexabrix 320 has a viscosity of 8.9 at 37°C, as compared to iothalamate meglumine 52% and iothalamate sodium 26% (40%I) which is approximately 9.0,iothalamate meglumine 60% (28.2%I) which is approximately 4.0, and diatrizoate meglumine 66% and diatrizoate sodium 10% (37%I) which has a viscosity of approximately 7.6 at 37°C.

INDICATIONS AND CLINICAL USAGE

Hexabrix 320 is indicated for use in cerebral angiography, peripheral arteriography, selective coronary arteriography with or without left ventriculography, pediatric angiocardiography, intravenous digital subtraction angiography and intravenous contrast enhancement of computed tomography of the brain and body. It is also indicated in phlebography, arthrography, excretory urography and hysterosalpingography.

Hexabrix 200 is indicated for use in phlebography, intra-arterial digital subtraction angiography, and for intravenous contrast enhancement of computed tomography of the body.

CONTRAINDICATIONS

Hexabrix is contraindicated for use in myelography and in any other intrathecal procedure. This preparation must not be used in patients with severe hepatic and renal disease and in patients with hypersensitivity to salts of ioxaglic acid. Refer to WARNINGS and PRECAUTIONS concerning hypersensitivity to other agents.

WARNINGS

Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events.

Numerous factors, including length of procedure, catheter and syringe material, underlying disease state and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Serious or fatal reactions have been associated with the administration of all iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction. As with any contrast medium, serious neurologic sequelae, including permanent paralysis, can occur following cerebral arteriography and injection into vessels supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors since they strongly potentiate neurologic effects.

A previous reaction to a contrast medium of different chemical structure or a history of iodine sensitivity is not an absolute contraindication to the use of Hexabrix if the examination is essential for the welfare of the patient. However, extreme caution should be exercised in injecting these patients and prophylactic therapy should be considered. (See PRECAUTIONS, General).

A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma. In such instances anuria has developed resulting in progressive uremia, renal failure and eventually death. Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be causative factors. The risk in myelomatous patients is not a contraindication to the procedure; however, partial dehydration in the preparation of these patients for the examination is not recommended since this may predispose to precipitation of myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing the effect. Myeloma, which occurs most commonly in persons over 40, should be considered before instituting intravascular administration of contrast agents.

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available.

Intravascular administration of contrast media may promote sickling in individuals who are homozygous for sickle cell disease. Fluid restriction is not advised. In patients with advanced renal disease, iodinated contrast media should be used with caution, and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure and recent renal transplant recipients may present an additional risk.

PRECAUTIONS

General

Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of a physician skilled and experienced in the particular procedure to be performed.

All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions are minor, life threatening and fatal reactions may occur without warning. The risk-benefit factor should always be carefully evaluated before such a procedure is undertaken. At all times a fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all severity, or situations which may arise as a result of the procedure, should be immediately available. If a serious reaction should occur, immediately discontinue administration and institute appropriate treatment. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for a least 30 to 60 minutes after administration.

Some severe, life-threatening reactions suggest hypersensitivity to the radiopaque agent, which has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established.

The possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered. A positive history of bronchial asthma or allergy, a family history of allergy, or a previous reaction of hypersensitivity to another contrast agent warrant special attention. Such a history, by suggesting histamine sensitivity and consequently proneness to reactions, may be more accurate than pre-testing in predicting the potential for reaction, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent, when a diagnostic procedure is thought essential, but calls for caution.

Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pre-test since in these patients the incidence of reaction is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection to be effective and should continue through the time of injection and for 24 hours after injection. Antihistamines should be administered within 30 minutes prior to the contrast medium injection. A separate syringe should be used for this injection because of chemical incompatibility.

The sensitivity test most often performed is the slow injection of 0.5 to 1.0 mL of the radiopaque medium, administered intravenously, prior to injection of the full dose. It should be noted that the absence of a reaction to the test dose does not preclude the possibility of a reaction to the full dose. If the test dose (or subsequent diagnostic injection) causes an untoward response, the examination should be terminated and appropriate measures taken to combat the adverse reaction. In rare instances, reactions to the test dose itself may be extremely severe; therefore, close observation of the patient, and facilities for emergency treatment, are indicated.

Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent and also in patients with occult renal disease, notably diabetics and hypertensives.

Administration of Hexabrix should be postponed in patients with hepatic or biliary disorder who have recently taken a cholecystographic agent. Especially in these classes of patients there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important fact influencing further renal impairment. Partial dehydration is not necessary, it may be dangerous, and is not recommended for uro-angiographic procedures. Consideration must be given to the functional ability of the kidneys before injecting this preparation because of the possibility of inducing or aggravating renal damage. An interval of at least 48 hours should be allowed between examinations, especially in patients with reduced renal reserve.

Caution should be exercised in performing contrast medium studies in patients with homocystinuria, endotoxemia and in those with elevated body temperatures. Acute renal failure has been reported in patients with diabetic nephropathy and in susceptible non-diabetic patients (often elderly with pre-existing renal disease) following administration of iodinated contrast agents. Careful consideration of the potential risks should be given before performing these radiographic procedures in these patients.

General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported in these patients, and may be attributable to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia which can prolong circulation time and increase the duration of contact of the contrast agent.

Reports of thyroid storm occurring following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of this drug. Iodine containing contrast agents may alter the results of thyroid function tests. Such tests, if indicated, should be performed prior to the administration of this preparation.

Special precaution is advised in patients with increased intracranial pressure, cerebral thrombosis or embolism, primary or metastatic cerebral lesions, subarachnoid hemorrhage, arterial spasm, transient ischemic attacks, and in any condition when the blood brain barrier is breached or the transit time of the contrast material through the cerebral vasculature is prolonged, since clinical deterioration, convulsions, and serious temporary or permanent neurological complications (including stroke, aphasia, cortical blindness, etc.) may occur following intravenous or intraarterial injection of relatively large doses of contrast media. Such patients, and patients in clinically unstable or critical condition should undergo examinations with intravascular contrast media only if in the opinion of the physician the expected benefits outweigh the potential risks, and the dose should be kept to the absolute minimum.

There have been reports in the literature indicating that patients on adrenergic beta-blockers may be more prone to severe adverse reactions to contrast media. At the same time, treatment of allergic-anaphylactoid reactions in these patients is more difficult. Adrenaline should be administered with caution since it may not have its usual effects. On the one hand larger doses of adrenaline may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex

11 bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of adrenaline include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.

Usage in Pregnancy: Category B

Reproduction studies have been performed in rats and rabbits at doses up to two times the maximum adult human dose and have revealed no conclusive evidence of impaired fertility or harm to the fetus due to Hexabrix. It is, however, known that Hexabrix crosses the placenta and reaches fetal organs and tissues. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:

Because contrast media are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Hexabrix, a decision should be made whether to discontinue nursing and substitute bottle feedings for breast feeding for a minimum of 24 hours following administration of this drug, or not to administer the drug taking into account the importance of the drug to the mother. (Precautions for specific procedures receive comment under that procedure).

ADVERSE REACTIONS

General:

NOTE: Since Hexabrix is an iodinated intravascular contrast agent, all of the side effects and toxicity associated with this class of compound are possible, and this should be borne in mind when Hexabrix is administered. Adverse reactions accompanying the use of iodine-containing contrast agents are usually mild and transient, although severe and life threatening reactions, including fatalities, have occurred. Because of the possibility of severe reactions to both the procedure and the radiopaque medium appropriate emergency facilities and well trained personnel should be available to treat both types. Emergency facilities and personnel should remain available for 30-60 minutes following the procedure since severe delayed reactions have been reported.

The most frequent adverse reactions are nausea, vomiting, facial flush and a feeling of body warmth. These are usually of brief duration.

Other reactions include the following:

Hypersensitivity Reactions:

Dermal manifestations of urticaria with or without pruritus, erythema and maculopapular rash, dry mouth, allergic glossitis, sweating, conjunctival symptoms, facial, peripheral and angioneurotic edema.

Symptoms related to the respiratory system include sneezing, nasal stuffiness, coughing, choking, dyspnea, chest tightness and wheezing, which may be initial manifestations of more severe and infrequent reactions including asthmatic attack, laryngospasm and bronchospasm with or without edema, pulmonary edema, apnea and cyanosis. Rarely, these allergic-type reactions can progress into potentially fatal anaphylactic shock with loss of consciousness and coma and severe cardiovascular disturbances.

Cardiovascular Reactions:

Generalized vasodilation, flushing and venospasm. Occasionally, thrombosis or rarely, thrombophlebitis. Extremely rare cases of disseminated intravascular coagulation resulting in death have been reported. Severe cardiovascular responses include rare cases of hypotensive shock, coronary insufficiency, cardiac arrhythmia, fibrillation and arrest. These severe reactions are usually reversible with prompt and appropriate management; however, fatalities have occurred.

Neurological Reactions:

Spasm, convulsions, aphasia, syncope, paresis, paralysis, visual field losses which are usually transient but may be permanent, coma and death.

Other Reactions:

Headache, trembling, shaking, chills without fever, hyperthermia and lightheadedness, renal shutdown or other nephropathy. Laboratory parameter changes include decreased lymphocytes, HB, RBC hematocrit, serum Na, Cl, K, Ca. Elevation of liver enzymes and bilirubin have been reported.

Technique Reactions: Extravasation with burning pain, hematomas, ecchymosis and tissue necrosis, vascular constriction due to injection rate, thrombosis and thrombophlebitis, bleeding, perforation and dissection of blood vessels, dislodgement of atheromatous plaques, and injury to neighbouring organs. (Adverse reactions to specific procedures receive comment under that procedure).

TREATMENT OF ADVERSE REACTIONS TO CONTRAST MEDIA

Contrast media should be administered only by physicians thoroughly familiar with the emergency treatment of all adverse reactions to contrast media. The assistance of other trained personnel such as cardiologists, internists and anesthetists is required in the management of severe reactions.

A guideline for the treatment of adverse reactions is presented below.

This outline is not intended to be a complete manual on the treatment of adverse reactions to contrast media or on cardio-pulmonary resuscitation. The physician should refer to the appropriate texts on the subject.

It is also realized that institutions or individual practitioners will already have appropriate systems in effect and that circumstances may dictate the use of additional or different measures.

For Minor Allergic Reactions: (if considered necessary).

The intravenous or intramuscular administration of an antihistamine such as diphenhydramine HCl 25-50 mg is generally sufficient (contraindicated in epileptics). The resulting drowsiness makes it imperative to ensure that out-patients do not drive or go home unaccompanied.

Major or Life-threatening Reactions:

A major reaction may be manifested by signs and symptoms of cardiovascular collapse, severe respiratory difficulty and nervous system dysfunction. Convulsions, coma and cardio-respiratory arrest may ensue.

The following measures should be considered:

1. Start emergency therapy immediately - carefully monitoring vital signs. 2. Have emergency resuscitation team summoned - do not leave patient unattended. 3. Ensure patent airway - guard against aspiration. 4. Commence artificial respiration if patient is not breathing. 5. Administer oxygen, if necessary. 6. Start external cardiac massage in the event of cardiac arrest. 7. Establish route for i.v medication by starting infusion of appropriate solution (5% dextrose in water). 14

8. Judiciously administer specific drug therapy as indicated by the type and severity of the reaction. Careful monitoring is mandatory to detect adverse reactions of all drugs administered: a) Soluble hydrocortisone 500-1000 mg i.v. for all acute allergic-anaphylactic reactions b) Adrenaline 1:1000 solution (in the presence of anoxia it may cause ventricular fibrillation; CAUTION in patients on adrenergic beta blockers. See PRECAUTIONS). i) 0.2-0.4 mL subcutaneously for severe allergic reactions. ii) in extreme emergency 0.1 mL per minute, appropriately diluted, may be given intravenously until desired effect is obtained. Do not exceed 0.4 mL. iii) in case of cardiac arrest 0.1-0.2 mL, appropriately diluted, may be given intracardially. c) In hypotension (carefully monitoring blood pressure): i) Phenylephrine HCl 0.1-0.5 mg appropriately diluted slowly i.v. or by slow infusion

Levarterenol bitartrate 4 mL of 0.2% solution in 1000 mL of 5% Dextrose by slow drip infusion. d) Sodium bicarbonate 5%; 50 mL i.v. every 10 minutes as needed to combat post-arrest acidosis. e) Atropine 0.4-0.6 mg i.v. to increase heart rate in sinus bradycardia. May reverse 2nd or 3rd degree block.

f) To control convulsions: i) Pentobarbital Sodium 50 mg in fractional doses slowly i.v. (contraindicated if cyanosis is present)

ii) Diazepam 5-10 mg slowly i.v. titrating the dose to the response of the patient.

9. Defibrillation, administration of antiarrhythmics and additional emergency measures and drugs may be required. 10. Transfer patient to intensive care unit when feasible for further monitoring and treatment.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

The adverse effects of overdosage are life-threatening and affect mainly the pulmonary, cardiovascular and central nervous systems. Treatment of an over-dosage is directed toward the support of all vital functions, and prompt institution of specific therapy. Ioxaglate salts are poorly bound to serum album and are excreted mainly through the kidneys.

DOSAGE AND ADMINISTRATION

It is advisable that Hexabrix be at or close to body temperature when injected. Discard unused portion. The patient should be instructed to omit the meal that precedes the examination, but it should be ensured that the patients are not dehydrated. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the X-ray exposure factors prior to the injection of the contrast medium.

If during administration a minor reaction occurs the injection should be stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately.

Under no circumstances should other drugs be administered concomitantly in the same syringe or i.v. administration set because of a potential for chemical incompatibility.

Sufficient time should be permitted to elapse between injections to allow for the subsidence of hemodynamic disturbances.

Patency of the vessel and the position of the catheter tip or needle should be checked with a small pilot dose before injecting the full dose. The catheter tip should be kept free of aspirated blood.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If either is present the vial should not be used.

Contrast media should not be transferred into other delivery systems except immediately before use.

CEREBRAL ANGIOGRAPHY

Hexabrix 320 may be used to visualize the cerebral vasculature by any of the accepted techniques.

Patient Preparation

Suitable premedication may be given. Introduction of the catheter or needle is normally performed with local anesthesia. General anesthesia is rarely required. (See PRECAUTIONS, General).

Precautions

In addition to the general precautions previously described, cerebral angiography should be performed with special caution in patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, senility, recent cerebral thrombosis, embolism or subarachnoid hemorrhage, and following a recent attack of migraine.

Adverse Reactions

The major sources of cerebral arteriographic adverse reactions appear to be related to repeated injections of the contrast material, administration of doses higher than those recommended, the presence of occlusive atherosclerotic vascular disease and the method and technique of injection.

Adverse reactions are normally mild and transient. A feeling of warmth in the face and neck is frequently experienced. Infrequently, a more severe burning discomfort is observed. Transient visual hallucinations have been reported.

Serious neurological reactions that have been associated with cerebral angiography include stroke, amnesia, hemiparesis, visual field loss, cortical blindness, aphasia, confusion, disorientation, hallucination, convulsions, coma and death.

Cardiovascular reactions that may occur with some frequency are bradycardia and either an increase or decrease in systemic blood pressure. The blood pressure change is transient and usually requires no treatment.

Usual Dosage

The usual adult dosage of Hexabrix 320 employed varies with the site and method of injection and the age and condition of the patient. The usual adult dose range for common carotid arteriography is 6-12 mL; for vertebral arteriography; 5-10 mL; for aortic arch injection (four vessel studies); 30-50 mL.

These doses may be repeated if indicated. The total dose per procedure should be limited to the smallest volume necessary to achieve a diagnostic examination.

INTRA-ARTERIAL DIGITAL SUBTRACTION ANGIOGRAPHY

Hexabrix 200 is a suitable agent for intra-arterial digital subtraction angiography (IA-DSA), since with this technique lower iodine concentrations yield diagnostic images. Other advantages of the procedure are the use of less contrast medium and a decreased need for selective arterial catheterization. However, with aortic arch injection visualization of the intracranial vasculature and small aortic branches may be insufficient.

Patient Preparation

No special patient preparation is required for IA-DSA. However, it is advisable to insure that patients are well hydrated prior to examination.

Precautions

In addition to the general precautions described, the risks associated with IA-DSA are those usually associated with cerebral arteriography and catheter procedures. Following the procedure, gentle pressure hemostasis is required, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture. Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies.

Usual Adult Dosage (using Hexabrix 200)

As a general rule, the volume and concentration used for IA-DSA are about 50%, or less, of that used for conventional procedures. The actual dosage and flow rate will vary depending on the selectivity of the injection site and the area being examined.

The following suggested volumes per injection are intended as a guide. Injections may be repeated if necessary. It is advisable to inject at rates approximately equal to the flow rate of the vessel being injected.

Carotid Arteries 6 - 10 mL Vertebral Arteries 4 - 8 mL Aortic Arch (4 vessel study) 25 - 50 mL Subclavian or Brachial Arteries 2 - 10 mL Femoral arteries 8 - 10 mL

PERIPHERAL ARTERIOGRAPHY

Hexabrix 320 may be injected to visualize the arterial peripheral circulation. Arteriograms of the upper and lower extremities may be obtained by any of the established techniques.

Patient Preparation The procedure is normally performed with local anesthesia. In rare instances, general anesthesia may be required (See PRECAUTIONS, General).

A preliminary radiograph is usually made prior to the injection of the contrast agent.

Precautions

In addition to the general precautions previously described, moderate decreases in blood pressure occur frequently with intra-arterial injections. This change is usually transient and requires no treatment, however, the blood pressure should be monitored for approximately 10 minutes following injection.

Extreme caution during injection of the contrast agent is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial disease (e.g. thromboangiitis obliterans, ischemia, thrombosis, obstruction). When injections are being made in the distal aorta for aorto-iliac run-off studies, the possibility of inadvertent injection of a large dose into a branch of the aorta or intra-mural dissection should be considered.

To prevent these occurrences, the position of the catheter tip or needle should be carefully evaluated. Pulsation must be present in the artery to be injected. A small dose of 1-2 mL should be administered to locate the exact site of the needle or catheter tip. Severe pain, paresthesia or peripheral muscle spasm during injection may require discontinuance of the procedure and a re-evaluation of the catheter tip or needle placement.

Great care is necessary to avoid entry of a large bolus into an aortic branch. Mesenteric necrosis, acute pancreatitis, renal shutdown and serious neurologic complications, including paraplegia and quadriplegia, have been reported and may be attributable to an excessive dose being injected into an aortic branch or arterial trunks supplying the spinal arteries or to prolonged contact time of the concentrated contrast medium on the CNS tissue. Conditions which can contribute to prolonged contact time include decreased circulation, aortic occlusions distal to the site of injection, abdominal compression, hypotension, general anesthesia or the administration of vasopressors. When these conditions exist or occur, the necessity of performing or continuing the procedure should be carefully evaluated and the dose and number of repeat injections should be maintained at a minimum with appropriate intervals between injections. Following catheter procedures, gentle pressure hemostasis is advised, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Adverse Reactions

In addition to the general adverse reactions previously described, extravasation, hematoma, gangrene, hemorrhage and thrombosis have occurred. Brachial plexus injury has been reported following axillary artery injection. Dissecting aneurysm, arteriovenous fistula are additional complications.

Usual Dosage

The single adult dose for aorto-iliac runoff studies is 20-60 mL: for common iliac, the external iliac and the femoral arteries 10-40 mL; for the upper limb 10-30 mL. These doses may be repeated if indicated. The total procedural dose should be limited to the smallest volume required to obtain a diagnostic examination.

SELECTIVE CORONARY ARTERIOGRAPHY WITH OR WITHOUT LEFT VENTRICULOGRAPHY

Precautions

In addition to the general precautions previously described, it is recommended that this procedure should not be performed for approximately 4 weeks following the diagnosis of myocardial infarction. Mandatory pre-requisites to the procedure are experienced personnel, ECG monitoring apparatus and adequate facilities for immediate resuscitation and cardioversion.

Patients should be monitored continuously by ECG and vital signs throughout the procedure. The injection of large volumes of hypertonic solutions into the heart chambers can cause significant hemodynamic changes.

Special care should be exercised in patients being treated with calcium ionantagonists, since in such circumstances a few instances of serious arrhythmias have been reported.

Adverse Reactions

Most patients will have transient ECG changes during the procedure. The following adverse effects have occurred in conjunction with the administration of iodinated intravascular contrast agents for this procedure: hypotension, shock, anginal pain, myocardial infarction, cardiac arrhythmias (bradycardia, ventricular tachycardia, ventricular fibrillation) and cardiac arrest.

Fatalities have been reported. Complications to the procedures include dissection of coronary arteries, dislodgement of atheromatous plaques, perforation, hemorrhage and thrombosis.

Usual Dosage 20

The usual adult dose range for left coronary arteriography is 2-10 mL and for right coronary arteriography is 1-8 mL. For left ventriculography, the usual single adult dose is 35-40 mL. These doses may be repeated if indicated; however, several minutes should be allowed to elapse between injections to allow for subsidence of hemodynamic disturbance, and the total procedural dose should be limited to the smallest volume necessary to obtain a diagnostic examination.

PEDIATRIC ANGIOCARDIOGRAPHY

Angiocardiography with Hexabrix 320 may be performed by any accepted technique.

Patient Preparation

Normal patient hydration should be maintained. Appropriate pre-medication should be given.

Warnings

In addition to general warnings previously described, the inherent risk of angiocardiography in cyanotic infants must be weighed against the necessity for performing this procedure. A dose of 10-20 mL may be particularly hazardous in infants weighing less than 7 kg. This risk is probably significantly increased if these infants have pre-existing right heart strain, heart failure and effectively decreased or obliterated pulmonary vascular beds.

Apnea, bradycardia and other arrhythmias, cerebral effects, electrolyte and hemodynamic disturbances are more likely to occur in cyanotic infants. Infants are more likely than adults to respond with convulsions, particularly after repeated injections.

Adverse Reactions

Injection of contrast media into the cardiac chambers or great vessels causes significant hemodynamic disturbances, especially in right sided injections. Depending on the injection site and the time of recording, significant changes include a drop in cardiac output, elevation or decrease in ventricular pressures (RVSP, LVSP, LVEDP, RVEDP), systemic pressure, peripheral hypotension, brady-or tachycardia, ectopic beats and other arrhythmias. If repeat injections are made in rapid succession, these changes are likely to be more pronounced.

It is suggested that hemodynamic changes be monitored and that pressures considered abnormal under roentgenographic conditions be allowed to return to a pre-angiographic level before continuation of radiopaque injection; this usually takes 15 minutes.

Precautions

Although contrast media of low osmolality, such as Hexabrix, are expected to cause less osmolality-related adverse effects and less subjective discomfort, such as pain, it is desirable that vital signs and laboratory parameters be closely monitored to detect immediate or delayed adverse effects (arrhythmias, electrolyte and hemodynamic disturbances).

Usual Dosage

The suggested average single dose of Hexabrix 320 is 1.0 mL/kg (range 0.5-2.0 mL/kg). The dose may be repeated if indicated. The total procedural dose should be limited to the smallest volume necessary to obtain a diagnostic examination and should not normally exceed 4 mL/kg. Sufficient time (approximately 15 minutes) should be allowed to elapse between injections to allow for subsidence of hemodynamic disturbances.

INTRAVENOUS DIGITAL SUBTRACTION ANGIOGRAPHY

Intravenous digital subtraction angiography (IV DSA) is a radiographic procedure which allows dynamic imaging of the arterial system following intravenous injection of iodinated X-ray contrast media through the use of image intensification, enhancement of the iodine signal and digital processing of the image data. Temporal subtraction of the images obtained prior to and during the "first arterial pass" of the injected contrast medium yield images which are devoid of bone and soft tissue.

Areas that have been examined by intravenous DSA are the arteries of the brachiocephalic circulation, the aortic arch, the abdominal aorta and its major branches including the arteries of the extremities.

Patient Preparation

No special patient preparation is required for IV DSA. However, it is advisable to insure that patients are well hydrated prior to examination.

Precautions

In addition to the general precautions previously described, the risks associated with IV DSA include intramural injections, and rupture or dissection of venous structures with extravasation into the tissues of extremities or the mediastinum. Small test injections of contrast medium made under fluoroscopic observation to insure the catheter tip is properly positioned, and in the case of peripheral placement that the vein is of adequate size, will reduce this potential. With high pressure injection, however, the catheter tip initially placed in a large venous structure may still recoil into a small tributary causing rupture of a small vein with extravasation into neighbouring tissues.

Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies. Therefore, patient cooperation is essential.

Adverse Reactions

Rupture of venous structures with tissue or mediastinal extravasation and severe pain. Thrombophlebitis, hypotension, arrhythmia, neurological complications and renal failure have been reported with IV DSA.

Usual Dosage

Hexabrix 320 may be injected intravenously for digital dynamic imaging of the arterial system following any established technique. The dose is usually administered by a venous catheter threaded into a large vein, the superior or inferior vena cava, using mechanical pressure injection or rapid manual injection.

Depending on the area to be imaged, the usual adult dose range per injection is 30 - 50 mL. Injections may be repeated if necessary. The total procedural dose should be kept to the smallest volume required to achieve a diagnostic examination and should not exceed 200 ml.

Injection rates will vary depending on the site of catheter placement and vessel size. Central catheter injections are usually made at a rate of between 10 and 25 mL/second. Peripheral injections are usually made at a rate of between 10 and 15 mL/second. Since a part of the injected medium can sometimes remain in the arm vein for an extended period, it may be advisable to flush the vein immediately following injection with an appropriate volume (20 - 25 mL) of 5% dextrose in water or normal saline.

INTRAVENOUS CONTRAST ENHANCEMENT IN COMPUTED TOMOGRAPHY (CT)

Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk, increased radiation exposure and may obscure certain lesions, should be based upon a careful evaluation of clinical, other radiological and unenhanced CT findings.

Computed Tomography of the Brain

Hexabrix 320 may be useful to enhance the demonstration of the presence and extent of certain malignancies such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas; ependymomas; medulloblastomas, meningiomas; neuromas; pinealomas; pituitary adenomas; craniopharyngiomas; germinomas; and metastatic lesions.

The usefulness of contrast enhancement for the investigation of the retrobulbular space and in cases of low grade or infiltrative glioma has not been demonstrated.

In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement. Maximum contrast enhancement of certain tumors may be delayed necessitating delayed scans.

Non-Neoplastic Conditions

The use of Hexabrix 320 may be beneficial in the image enhancement of non-neoplastic lesions. Cerebral infarctions of recent onset may be better visualized with the contrast enhancement, while some infarctions are obscured if contrast media are used. The use of iodinated contrast media results in contrast enhancement in about 60% of cerebral infarctions studied from one to four weeks from the onset of symptoms. Sites of active infection may also be enhanced following contrast medium administration.

Arteriovenous malformations and aneurysms will show contrast enhancement. In the case of these vascular lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.

Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement. However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast medium administration may be helpful in ruling out the possibility of associated arteriovenous malformation. (Also see Precautions).

The opacification of the inferior vermis following contrast medium administration has resulted in false positive diagnoses in a number of normal studies.

Usual Dosage

For adults the usual dosage of Hexabrix 320 is 1.0 - 2.0 mL/kg, not exceeding 150 mL.

Body Computed Tomography

Hexabrix 320 or Hexabrix 200 may be administered when necessary for contrast enhancement of the organs, tissues and blood vessels of the chest, abdomen and pelvis. Continuous or multiple scans separated by intervals of 1 - 3 seconds during the first 30 - 90 seconds post-injection of the contrast medium (dynamic CT scanning) are required to demonstrate enhanceable lesions. Subsets of patients in whom delayed body CT scans might be helpful have not been identified.

Inconsistent results have been reported and abnormal and normal tissues are usually isodense during the time frame used for delayed CT scanning. The risks of such indiscriminate use of contrast media are well known and such use is not recommended. At present, consistent results have been documented using dynamic CT techniques only.

Warning

Patients with diabetes mellitus and impaired renal function are considered to be at greater risk of developing acute renal failure following the injection of large doses of contrast media required for contrast enhancement in CT scanning.

Convulsions and other serious neurologic complications have occurred in patients with primary or metastatic cerebral lesions or breached blood brain barrier following the administration of iodine-containing radiopaque media for enhancement of CT brain images.

Patient Preparation

No special patient preparation is required for contrast enhancement in computerized tomography. However, it is advisable to insure that patients are well hydrated prior to examination. In patients undergoing abdominal or pelvic examination, opacification of the bowel by dilute oral contrast medium may be valuable in scan interpretation.

Precautions

In addition to the general precautions previously described, it is advisable to insure that patients are adequately hydrated prior to examination. Patient motion, including respiration, can markedly effect image quality, therefore, patient cooperation is essential. The use of an intravascular contrast medium can obscure tumors in patients undergoing CT evaluation resulting in a false negative diagnosis.

Usual Adult Dosage

Hexabrix 320 may be administered by bolus injection, rapid infusion or by a combination of both. Depending on the area to be examined, doses of 30 - l50 mL (0.5 - 2.0 mL/kg) may be administered. When prolonged enhancement is required up to 150 mL can be used, usually with 25 - 50 mL as a rapid bolus and the remainder as an infusion.

Hexabrix 200 has been used in CT of the thorax at single doses of 60 ml. For prolonged enhancement a total dose of up to 200 mL has been used, with 40 to 80 mL as a rapid bolus and the remainder as an infusion.

PHLEBOGRAPHY

Hexabrix 320 and Hexabrix 200 may be used to visualize the peripheral venous circulation. Venograms are obtained by injection or infusion into an appropriate vein in the upper or lower extremity.

Precautions

In addition to the general precautions previously described, special caution is advised when venography is required in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a significantly obstructed venous system.

Extreme caution is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease.

Complications of the procedure include bleeding, thrombosis, thrombophlebitis, gangrene and major systemic adverse reactions.

Usual Dosage

The usual single dose for adults is 40 - 60 mL of full strength (32% iodine) Hexabrix 320 as a single injection for the lower extremity and 10 - 20 mL for an upper extremity.

Hexabrix 200 may also be employed. Opacification of the deep veins may be less than with a more concentrated contrast material. The usual dose of Hexabrix 200 will range from 50 - 100 mL for the lower extremity, and 15 - 30 mL for the upper extremity.

Following the procedure, the venous system should be flushed with normal saline. Massage and elevation are also helpful for clearing the contrast medium from the extremity.

EXCRETORY UROGRAPHY

Following intravenous injection, Hexabrix 320 is rapidly excreted by the kidneys. Hexabrix 320 may be visualized in the renal parenchyma one minute following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 7 to 12 minutes after injection. In patients with severe renal impairment, contrast visualization may be substantially delayed, or may not occur at all. With low osmolar contrast media, the collecting system may be less distended and appear more dense. The nephrographic effect may be less pronounced.

Patient Preparation

A low residue diet the day preceding the examination and a laxative the evening before the examination may be given, unless contraindicated. Partial dehydration is not recommended and may be dangerous. Maintenance of normal hydration is desirable.

Precautions

Adequate renal function must be present. Dehydration will not improve contrast quality in patients with impaired renal function and will increase the risk of contrast induced renal damage. (Also see WARNINGS and PRECAUTIONS, General, concerning preparatory dehydration).

Usual Dosage

The usual dose range of Hexabrix 320 is 0.5 to 1.0 mL/kg, amounting to a single dose of 50 mL in the average normal adult. The dose is injected intravenously, usually within 30 to 90 seconds.

ARTHROGRAPHY

Preliminary experience with Hexabrix 320 indicates that filling of narrow fissures and tears may be delayed necessitating more massage and delayed films. The rate of contrast medium absorption as well as the production of synovial fluid and consequent dilution of the medium may be reduced.

Precautions

In addition to the general precautions previously described, strict aseptic technique is required to prevent the introduction of infection. Arthrography should not be performed when there is infection in or near the joint. Fluoroscopic control should be used to insure proper introduction of the needle into the synovial space and prevent extracapsular injection, which is painful and may lead to incapacity lasting 24 - 48 hours. Aspiration of excessive synovial fluid will reduce the pain on injection and prevent the dilution of the contrast agent. It is important that undue pressure not be exerted during the injection.

Adverse Reactions

In addition to the general adverse reactions previously described, arthrography may induce joint pain or discomfort which is usually mild and transient but occasionally may be severe and persist for 24 to 48 hours following the procedure. Effusion requiring aspiration may occur. Systemic adverse reactions have occurred.

Usual Dosage

Arthrography is usually performed under local anesthesia. The amount of contrast agent required is dependent on the size of the joint to be injected and the technique employed.

The following dosage schedule for normal adult joints should serve only as a guide since joints may require more or less contrast medium for optimal visualization.

Knee, hip, shoulder 5 - 15 mL Temporomandibular 0.5 to 0.7 mL

Massage, passive or active manipulation is necessary to disperse the medium throughout the joint space and to insure that small tears are well outlined with the contrast material.

Lower volumes of contrast medium are usually employed for double contrast examinations in which either filtered room air or carbon dioxide may be introduced for examination of the joints.

HYSTEROSALPINGOGRAPHY

Patient Preparation

It is preferable to perform the procedure approximately eight to ten days after the onset of menses. The patient should empty the bladder before the examination.

Precautions

Caution should be exercised in patients suspected of having cervical, uterine or tubal carcinoma to avoid possible spread of the lesion by the procedure. The procedure is contraindicated in pregnancy. The examination should not be performed during the menstrual period or when infection is present in any portion of the genital tract; its use is not advised for 6 months after termination of pregnancy or 30 days after cervical conization or endometrial curettage. Delayed onset of pain and fever (1-2 days) may be indicative of pelvic infection.

Adverse Reactions In addition to the general adverse reactions described previously, fever and pain, cramping and tenderness of the abdomen have been reported. Systemic reactions may occur.

Usual Dosage The total volume administered will vary depending upon anatomical variations and/or disease processes. The usual dose varies from 5 to 10 mL, administered slowly through a cannula under fluoroscopic control, without undue pressure. 28

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Ioxaglic Acid

Chemical Name:

N-(2-hydroxyethyl)-2,4,6-triiodo 5-{2-[5-methylcarbamyl 2,4,6-triiodo 3-(N-methylacetamido)benzamido]acetamido}isophtalamic acid.

Molecular Formula:

C24H21N5O8I6

Molecular Weight: 1269

Description:

Appearance: White powder, odorless. Solubility: Ioxaglic Acid is slightly soluble in water, alcohol, ether, chloroform and methanol, but very soluble in dimethyl formamide. pKa: The pKa of Ioxaglic Acid is 2.97.

Thermal Analysis: Ioxaglic Acid decomposes at temperatures of 300oC or greater.

Composition: Hexabrix injectable solution characteristics:

Hexabrix solutions are clear, colourless to pale yellow containing no undissolved solids. Crystallization does not occur at normal room temperatures. It is supplied in containers from which has been displaced by nitrogen.

Hexabrix is a sterile, non-pyrogenic, aqueous solution of the meglumine salt and the sodium salt of ioxaglic acid in a 2:1 ratio.

The two salts have the following structural formula:

The pH of the Hexabrix formulation is adjusted to between 6.0 and 7.6.

Concentrations/mL:

Each millilitre of Hexabrix 320 contains 393 mg of ioxaglate meglumine, 196 mg of ioxaglate sodium and 0.10 mg edetate calcium disodium as a stabilizer. The solution contains 3.48 mg (0.15 mEq) sodium in each millilitre and provides 32% (320 mg/mL) organically bound iodine.

Hexabrix 200 contains in each millitre 246 mg of ioxaglate meglumine, 123 mg of ioxaglate sodium and 0.1 mg of edetate calcium disodium as a stabilizer. The solution contains 2.2 mg (0.095 mEq) sodium in each millilitre and provides 20% (200 mg/mL) organically bound iodine.

Solutions of ioxaglate (Hexabrix) provide six iodine atoms for each two dissociated ions. Conventional iodinated contrast agents provide only three iodine atoms for each two dissociated ions. Since osmolality is related to the number of ions in solution, Hexabrix has an osmolality of about one third the osmolality of traditional iodinated contrast agents at equivalent iodine concentrations. The osmolality of Hexabrix 320 is approximately 600 m0sm/kg, that of Hexabrix 200 is 356 mOsm/kg.

Hexabrix 320 has a viscosity (cps) of 14.7 at 25°C and 8.9 at 37°C. Hexabrix 200 has a viscosity (cps) of 3.5 at 25°C and 2.5 at 37°C.

At the time of manufacture, the pH is adjusted to 6.0 to 7.6.

Availability

Hexabrix 320 is available in 20 mL vials in boxes of 50, in 25 mL in 50 mL vials in boxes of 50, in 30 mL vials in boxes of 50, in 50 mL vials in boxes of 50, in 75 mL in 150 mL bottles in boxes of 12, in 100 mL in 150 mL bottles in boxes of 12, in 150 mL bottles in boxes of 12 and in 200 mL in 250 mL bottles in boxes of 12.

Hexabrix 200 is available in 20 mL vials in packages of 24, in 50 mL vials in packages of 24, in 100 mL in 150 mL bottles in boxes of 12, in 150 mL bottles in packages of 12 and in 200 mL in 250 mL bottles in packages of 12.

PHARMACY BULK VIAL FOR HEXABRIX 320 (500 mL BOTTLE)

For Multiple Dispensing

This Bulk Pharmacy Vial is intended for multiple dispensing for intravascular use only, it must be spiked only once.

Directions for Use

Use proper aseptic techniques when handling injection device for maintenance of sterility during multiple dispensing contrast agent at room temperature.

The availability of the Bulk Pharmacy Vial is restricted to hospitals with a recognized intravascular admixture program for multiple dispensing or for use of diluted solution. Once punctured, use the contents of the Pharmacy Bulk Vial within four hours and diluted solutions within 24 hours if kept at room temperature, and 72 hours if refrigerated from the time of initial puncture.

STABILITY AND STORAGE

Recommendations

Store between 15-30oC. Protect from light. Protect from freezing. Discard unused portion. Submersion of syringes in water is not recommended. Do not re-autoclave plastic container because of possible damage to syringe. 32

PHARMACOLOGY

As already mentioned under Clinical Pharmacology, Hexabrix (ioxaglate) is excreted by the kidneys in unchanged form. It disappears from the blood in a biphasic manner. This has been confirmed in the dog and the rat although in the latter biliary excretion plays a major role (30% in the rat). Hexabrix is excreted via glomerular filtration without tubular secretion. However, there is a possibility of some net tubular reabsorption. High doses of Hexabrix do not appear to alter glomerular filtration or renal tubular secretory functions.

Hexabrix undergoes a much greater degree of biliary excretion than Na/Meglumine diatrizoate 32% I in the rat and both contrast agents appear to be excreted in unchanged form. The biliary excretion of Hexabrix appears to be capacity limited.

The relative degree of choleresis associated with biliary excretion of ioxaglate, compared to that associated with diatrizoate, is less than might be anticipated on the basis of differences in biliary concentration of contrast media and is apparently due to the lower osmolality of ioxaglate.

A study on the distribution of ioxaglate and diatrizoate in the pregnant mouse have shown that both compounds were capable of crossing the placental barrier and invading fetal tissue. Hexabrix and sodium diatrizoate both show only a low level of protein binding.

In the anesthetized dog, after intravenous injection of 1 mL/kg, hemodilution with Hexabrix was about one half of that with Na meglumine diatrizoate 32%I. In a comparative in vitro study of ioxaglic acid 16%I, diatrizoic acid 6%I and iothalamic acid 6%I, it was found that ioxaglic acid and iothalamic acid both produced an increase in red blood cell oxygen affinity, whereas diatrizoic acid had a less marked but more prolonged effect.

Ioxaglic acid and diatrizoic acid activated both the classical and alternative complement pathways. Maximum C3 conversion was induced by both agents at a concentration of approximately 0.005M. Neither contrast medium induced significant release of lactic dehydrogenase from mouse peritoneal macrophages.

At concentrations of greater than 10-4M both evoked a significant release of lysosomal beta glucuronidase and beta galactosidase. In dogs, internal carotid injection of Hexabrix 1 mL/kg was well tolerated and showed lesser effects on blood pressure, heart rate, cardiac output and stroke volume than did diatrizoate 32. Similarly, injection of Hexabrix (4, 6 and 8 mL) into the left coronary artery of dogs caused less hypotension, changes in cardiac output and stroke volume, increases in coronary flow and ECG changes, with the exception of bradycardia, then Na meglumine diatrizoate 37 (37% iodine).

There was a statistically significant difference between Hexabrix and diatrizoate 32 on coronary flow only. The effects of right coronary artery injection of 0.4, 0.7 and 1.0 mL of Hexabrix elicited ECG alterations, blood pressure changes and transient bradycardia.

Hexabrix and sodium ioxaglate caused the least bradycardia, while diatrizoate 32 and 37 provoked a notable and sometimes prolonged bradycardia in 15% and 30% of the animals tested, respectively.

When large doses (3 mL/kg) were injected into the right atrium in dogs, there was much less effect on systemic and pulmonary hemodynamics (as judged by blood pressure, left ventricular pressure, cardiac output, pulmonary arterial pressure and pulmonary arterial flow) with Hexabrix than with Na meglumine diatrizoate 32 or 37 with the exception of electrophysiological disturbances which were statistically significant compared with DIA 37 only. When 10 mL were injected into the left renal artery of dogs, there was biphasic vasodilatation followed by vasoconstriction. These effects were less pronounced with Hexabrix than with Na meglumine diatrizoate 37, but similar to those with Na meglumine diatrizoate 32. Dog femoral artery injections of Hexabrix showed much less vasodilatation than did diatrizoate 37. This appeared to be directly related to the lower osmolality of Hexabrix solutions. Injection of Hexabrix 320 into the right coronary artery of rabbits also showed less cardiovascular toxicity than did Na ioxaglate (32% iodine).

No significant differences were observed in the hypotensive response to the various contrast media, although Hexabrix, Na ioxaglate and diatrizoate 32%I tended to cause a lesser degree of hypotension compared to Na ioxaglate and diatrizoate 37%.

In guinea pigs, intracarotid injection of 1 mL of Hexabrix 320 showed EEG changes of less magnitude than 1 mL of diatrizoate 32 and caused less pronounced painful reactions than 1 mL diatrizoate 32 or sodium ioxaglate.

Blood brain barrier lesions were not observed in any guinea pigs after intracarotid administration of ioxaglic acid at concentrations of up to 40%I. Damage to the barrier integrity was seen in 1 out of 4 guinea pigs following intracarotid injection of 1 mL of Na ioxaglate 42%I.

Hexabrix 320 had no significant effect on bronchoconstriction at doses of up to 10 mL/kg (3200 mgI/kg), although a slight increase was observed at each dose level. Injection of Na meglumine diatrizoate 32%I at doses of 5 and 10 mL/kg caused significant dose related increases in bronchopulmonary pressure with maximal effects observed from 5 to 10 minutes after treatment. 34

TOXICOLOGY

Acute Studies

Intravenous LD50s, stated as grams of iodine/kg, were as follows for the stated animals: mice 10.5 to 12.8, rats 8.0, rabbits 6.4, dogs 10.24 and neonatal rabbits 8.0. LD50s for acute intraperitoneal toxicity was 22.4 gI/kg in mice and 8 gI/kg in rats. LD50s for acute intracerebral toxicity in the mouse was 355 mgI/kg. Clinical signs included hyperreflexia and convulsions.

Mice at 12.8 gI/kg (1 mL/min) showed immediate decrease in motor activity accompanied by increased respiratory rate, prostration and unconsciousness. Male mice showed coarse tremors and toxic convulsions. Autopsy of two deceased animals showed either congestion of somatic tissues or rupture of a mesenteric blood vessel (considered to be injection artifacts). The i.v. LD50 (2 mL/min) with Hexabrix was markedly higher (37.94 to 40.24 mL/kg) than diatrizoate 32 (21.94 to 32.06 mL/kg). At low dosages the latent period before death was 3 days with Hexabrix and 8 hours with diatrizoate 32. Following the highest doses, mice died a few hours after receiving Hexabrix 320 and within a few minutes after diatrizoate 32.

Rats at 8.0 gI/kg (1 mL/min) showed subnormal weight gain over a 14 day observation period. Rats at 8.0 gI/kg (2 mL/min) showed piloerection, rigidity, hypoactivity and tachypnea within 5 hours. Weight gain pattern remained normal. Occasional hypoactivity was present on the second day. "Darkening of the eyes" occurred, especially in males up to 1 hour after injection.

Rats received the maximum injectable intraperitoneal dose of 25 mL/kg of Hexabrix 320 showed hypoactivity and occasional blood staining of the snout lasting for three days. Three animals died, and necropsy revealed fluid in the peritoneal cavity, lung congestion and hepatic darkening. The survivors had a slightly subnormal weight gain over the 14 days observation period.

Rabbits at 6.4 gI/kg/day (1 mL/min) showed no adverse effects and weight gains were normal. Fourteen day old rabbits showed some immediate deaths (4 out of 15) at 8 gI/kg. Necropsy revealed internal hemorrhage. Survivors at the dose showed hyperactivity, tremor, bleeding from the nose, convulsions and unconsciousness recovering in 1 hr.

Dogs showed slight edema of the injection site at 1.28 or 5.12 gI/kg for 3 days. Marked edema with discoloration was seen at 6.4 to 10.24 gI/kg, lasting for 3 to 8 days, vomiting occurred at 10.24 gI/kg.

LONG TERM STUDIES

In a preliminary range-finding study in rats, the growth performance of animals receiving 4 or 8 mL/kg/day of Hexabrix 320 was slightly inferior to that of controls although feed intake was unaffected. A dose-related incidence of tissue damage including necrosis at the injection site was observed. Pallor of the kidneys was also seen. Rats on Hexabrix i.v. from 480 mgI/kg/day for 4 weeks showed globular eosinophilic intracytoplasmic inclusions in proximal renal tubule cells, which resolved 4 weeks after treatment termination in females, but persisted in males although reduced in size and number. Electron microscopic examination of the renal cortex showed a marked increase in the number and size of heterophagic vacuoles secondary lysosomes, and loss of nuclei in the renal proximal tubules in treated but not in control animals. Except for 3 deaths which occurred during retro-orbital sinus blood sampling, no animals died during treatment. Those deaths were not treatment-related. Hexabrix 320 produced dose-related effects at the injection site ranging from erythema at low dose to ulceration of the tail in some rats at intermediate and high doses. Subcutaneous or intramuscular injection caused local inflammatory changes and muscle degeneration. Hematological evaluation after 3 weeks of treatment revealed minor reductions in erythrocytic parameters (packed cell volume, hemoglobin content, red blood cell count or mean corpuscular volume) and serum proteins (total protein, albumin or globulins) in male and female rats treated with 6.0 mL Hexabrix 320/kg/day. After 4 weeks of treatment, erythrocytic characteristics and serum protein concentrations were unaffected in rats receiving 1.5 or 3.0 mL Hexabrix 320/kg/day except for slightly reduced mean corpuscular volume in females in the 3 mL/kg/day group.

Treatment with Hexabrix 320 had no effect on leukocyte characteristics, blood chemistry (electrolytes, urea, glucose, alkaline phosphatase and glutamate- pyruvate transaminase) or urinalysis. Microscopic examination at necroscopy showed scale loss and congestion at the injection site accompanied byulceration and occasional necrosis at the intermediate and highest doses. In the rat, a decrease in thyroid weight in females, a decrease in prostate weight in males, a small increase in kidney weight in males and females, a decrease in body weights in males and females, a decrease in body weights and absolute lung weights of some females and an increase in relative brain and liver weights of some females were seen.

Dogs on Hexabrix 320 i.v. from 640 mgI/kg/day to 2560 mgI/kg/day showed eosinophilic intracytoplasmic inclusions in epithelial cells of proximal renal tubules. The size and number of inclusions was dose related. Four weeks after stopping treatment, no microscopic renal abnormalities were seen in the highest dosage group.

These changes have also been observed following injection of the currently used intravascular ionic and non-ionic contrast media and were reversible with these agents. General observation revealed no adverse effects of Hexabrix 320 treatment except for vomiting in one female during administration of the first 4.0 mL/kg dose. Bruising, perivascular swelling and/or inflammation were observed at the injection sites for all dogs including saline controls. These lesions were usually minimal with usually complete recovery within 72 hours. 36

The occurrence and severity of the lesions were not treatment or dose related. Erythrocyte hemoglobin or cell counts were reduced slightly in female dogs after 3 weeks of Hexabrix 320 treatment compared to saline controls. However, the values were similar to those of pre-treatment control observations for each group.

Hexabrix 320 treatment has no effect on blood chemistry or urinalysis determinations after 3 weeks of treatment. An increased prostate/body weight ratio was seen in the highest dosed group. Generlized renal pallor, slivghtly increased kidney weights (female), decreased thyroid weight (male) were also seen.

Mutagenicity

Hexabrix or its potential metabolites are not mutagenic based on the results of an Ames test and the ability to induce phage activity in lysogenic bacteria. Hexabrix 320 administration to male rats at single doses up to 8 mL/kg/day (2560 mgI/kg) had no adverse effects upon fertility or pre- and post-implantation of zygotes in females mated with treated males. These data indicate that Hexabrix 320 does not incude dominant mutations in germ cells of male rats.

Reproduction and Teratology

Daily intravenous treatment of Hexabrix 320 to rats had no consistent adverse effects upon reproductive function, fertility, pregnancy or offspring development. Hexabrix does not have teratogenic effects in the rat following subacute administration of large doses. Daily intravenous administration of Hexabrix 320 at dose levels up to 8 mL/kg/day (2560 mgI/kg/day) to sexually mature female rats (Fo) for 15 days before pairing and throughout mating, gestation and lactation periods has no adverse effect upon mating performance development, fertility, conception rate, viability, sex ratio, growth and physical development, auditory and visual functions and behavioural response of the offspring. Necropsy of offspring (F1) revealed no gross abnormalities and no dose-related effect was observed on thyroid weights. Pups from the 16 mL/kg/day group succumbed within 96 hours post-partum and necropsy revealed possible palatine defects, however, no definitive diagnosis was possible due to extensive autolysis. After weaning, the growth, mating performance and fertility of F1 animals were unaffected. Viability, sex ratio, auditory and visual functions, behavioural responses, growth and physical development profile, with the exception of pinna unfolding were similar in F2 offspring derived from all treatment groups. Pinna unfolding was slightly delayed in F2 offspring derived from 4 and 8 mL/kg/day of Hexabrix treatment groups.

The results of a study on pregnant rats receiving daily intravenous doses of Hexabrix 320 up to 8.0 mL/kg/day from day 5 through day 17 of gestation showed no adverse effects on pregnancy or offspring development. Necropsy of dams (2 mL/kg/day) after incidence of total litter loss revealed mammary tissue that was unable to produce milk. This was not observed at the higher dose level and was considered incidental and not treatment related. Five offspring with umbilical hernia were observed, one each in the saline control group, 4 an 8 mL/kg/day Hexabrix group, and 2 in the 2 mL/kg/day Hexabrix group. 37

Treatment of pregnant rabbits with Hexabrix 320 at doses of 4.0 and 8.0 mL/kg/day from days 6-18 of gestation may be associated with a slight increase in fetal loss due to abortion. The incidence of post-implantation loss appeared to be slightly increased in doses treated with Hexabrix; however, due to an inconsistent dose-relationship, it cannot be ascertained whether post-implantation loss was attributable to treatment. At necropsy, no abnormalities (maternal) were attributable to treatment with Hexabrix. Examination of foetuses post-mortem and following skeletal processing, revealed a number of abnormalities (abnormal ribs, cervical and thoracic vertebrae, spina bifida, bilateral forelimb flexure and curving of long bones in hind feet, separation of 2nd and 3rd digit of right foot, one claw missing from hind foot) in the treated group. These abnormalities were non-dosage related. While high doses of Hexabrix may enhance the incidence of spontaneous aborting, and post-implantation loss, such treatment regimens do not appear to have teratogenic effects. 38

BIBLIOGRAPHY

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